Early skin toxicity predicts better outcomes, and early tumor shrinkage predicts better response after cetuximab treatment in advanced colorectal cancer.

Cetuximab-containing treatments for metastatic colorectal cancer have been shown to have higher overall response rates and longer progression-free and overall survival than other systemic therapies. Cetuximab-related manifestations, including severe skin toxicity and early tumor shrinkage, have been shown to be predictors of response to cetuximab. We hypothesized that early skin toxicity is a predictor of response and better outcomes in patients with advanced colorectal carcinoma. We retrospectively evaluated 62 patients with colorectal adenocarcinoma who had unresectable tumors and were treated with cetuximab in our institution. Skin toxicity grade was evaluated on each treatment day. Tumor size was evaluated using computed tomography prior to treatment and 4-8 weeks after the start of treatment with cetuximab.Patients with early tumor shrinkage after starting treatment with cetuximab had a significantly higher overall response rate (P = 0.0001). Patients with early skin toxicity showed significantly longer overall survival (P = 0.0305), and patients with higher skin toxicity grades had longer progression-free survival (P = 0.0168).We have shown that early tumor shrinkage, early onset of skin toxicity, and high skin toxicity grade are predictors of treatment efficacy and/or outcome in patients with advanced colorectal carcinoma treated with cetuximab.

Salvage of a massive esophago-tracheal fistula resulting from a stenting treatment.

We report the successful surgical resolution of a case of massive esophago-tracheal fistula (ETF) caused by a stenting treatment for stricture of an esophago-gastric anastomosis. A 54-year-old man was admitted to our hospital due to serious pneumonia secondary to ETF. He had previously received esophagectomy and post-operative chemo-radiation therapy for esophageal cancer, followed by stenting treatments for a benign stricture of the esophago-gastric anastomosis. For surgical treatment of the resulting ETF, serial operations were required. The first operation, performed under percutaneous cardiopulmonary support, included removal of the stents followed by tracheotomy, were with the coverage of the tracheal defect achieved using both major pectoral muscle flaps. A salivary fistula was also generated and an enteral nutrition tube was placed. Six months after the first operation, a pedicled ileocolic interposition was performed in order to effect reconstruction of the digestive tube, with an additional microvascular anastomosis of the ileocolic and internal thoracic artery and vein. After the second operation, the patient's ability to ingest food was restored, and he was discharged from the hospital. Thus, ETF was successfully treated by successive surgical operations with delicate intra- and post-operative respiratory management.

Delayed esophageal reconstruction for aortoesophageal fistula caused by an aortic arch aneurysm with microvascular anastomosis of the left gastric artery and vein.

SUMMARY: We report a case of aorto esophageal fistula (AEF) with delayed esophageal reconstruction employing microvascular anastomosis. We demonstrate here that our method is useful for delayed esophageal reconstruction following AEF.

Mediastinal bronchial artery aneurysm with hematemesis.

Mediastinal bronchial artery aneurysm is a rare condition which can lead to potentially fatal hemorrhage. In most cases it presents respiratory symptoms due to rupture into pleural parenchyma. But when it develops mediodorsally and compresses the esophagus, it may cause dysphagia or hematemesis. Here we report a case of mediastinal bronchial artery aneurysm which presented with hematemesis. Computed tomography and endoscopic ultrasound showed what seemed to be a submucosal tumor on the esophagus. We were able to correctly diagnose the aneurysm using magnetic resonance imaging and probe thoracoscopy, and were able to successfully treat with transluminal artery embolization.

Regional myocardial function at the papillary muscle insertion site.

The importance of the mitral apparatus to the global left ventricular (LV) function has been suggested in several clinical studies. One recent study reported that chordal transsection induced an unloading of myocardium at the papillary muscle insertion site. We hypothesized that the regional response for afterloading at this site with intact mitral apparatus was different from that at the free wall. We investigated the end-systolic pressure-regional segment length relations (ESPLR) in two anterior LV sites, free wall (FREE) and the papillary muscle insertion site (PAP), during an increasing afterload by aortic occlusion in 7 anesthetized open-chest dogs. To measure the regional segment length at FREE and PAP, two sets of the pair of sonomicrometer crystals were implanted in the same midwall depth at the same circumferential hoop by using an echocardiographic guide. ESPLR both at FREE and PAP were always highly linear in a physiological range (r > or = 0.9). The slope of this relation at FREE (274 +/- 164 mmHg/mm) was significantly steeper than that at PAP (157 +/- 118 mmHg/mm) for each dog (p < 0.05). These data indicate that the regional response for afterloading at PAP loaded by chordal tension is different from that at FREE in the same heart.

Factors associated with increased extravascular lung water in cardiac tamponade and myocardial ischemia.

OBJECTIVE: To evaluate and compare the factors associated with pulmonary edema in cardiac tamponade and myocardial ischemia. DESIGN: Prospective, controlled laboratory study. SETTING: Animal research laboratory of a university hospital. SUBJECTS: Fourteen anesthetized dogs. INTERVENTION: Extravascular lung water (EVLW) was measured with thermal indocyanine green dye double-indicator dilution method and hemodynamic indices were determined by the pulmonary artery flotation catheter. Seven dogs were used in the tamponade model, and seven other dogs were used in the myocardial ischemia model. Furthermore, ten dogs were dedicated to measure plasma colloid osmotic pressure (COP) and blood gas analysis during cardiac tamponade and myocardial ischemia. MEASUREMENTS AND MAIN RESULTS: Mean right atrial pressure (MRAP) (7-->10 mm Hg), pulmonary capillary wedge pressure (PCWP) (10-->13 mm Hg), and EVLW (5.4-->10.1 mL/kg) increased during tamponade, but all of these indices returned to the control level after release of tamponade (MRAP, 7 mm Hg; mean PCWP, 11 mm Hg; mean EVLW, 5.2 mL/kg). Myocardial ischemia caused increases in PCWP (10-->14 mm Hg) and EVLW (5.6-->9.6 mL/kg). Although PCWP returned to the control level, EVLW remained elevated (9.2 mL/kg) after reperfusion. EVLW had good correlations with MRAP (r2 = .64, p < .05) and PCWP (r2 = .62, p < .05) during cardiac tamponade. Despite a fair correlation between EVLW and PCWP during ischemia (r2 = .73, p < .05), EVLW was not related to PCWP after reperfusion. COP decreased during myocardial ischemia and at the reperfusion period, but there was no significant change in COP in the cardiac tamponade model. CONCLUSIONS: In contrast to a close relation between hydrostatic pressure and EVLW in cardiac tamponade, hydrostatic pressure was not a determinant of pulmonary edema during the reperfusion period after myocardial ischemia.

Long-term administration of atrial natriuretic peptide in patients with acute heart failure.

A short-term treatment of atrial natriuretic peptide (ANP), a circulating hormone of cardiac origin, is reported to improve cardiac performance in patients with chronic heart failure. However, clinical usefulness of long-term administration of ANP in patients with congestive heart failure has not been reported. We studied 36 patients with severe acute heart failure who resisted various therapy. Hemodynamic parameters were measured before and 48 h after initiating ANP infusion (n = 18) or normal saline (n = 18). Mean pulmonary capillary wedge pressure (23-->13 mm Hg), mean right atrial pressure (10-->5 mm Hg), systemic vascular resistance (2,169-->1,307 dyn x s x cm(-5)) and pulmonary vascular resistance (318-->136 dyn x s x cm(-5)) decreased significantly, whereas cardiac index (1.9-->2.6 L/min/m2) and urine volume (1,692-->2,560 ml/day) increased during long-term ANP infusion (before-->48 h). Moreover, in eight patients with long-term ANP infusion, these hemodynamic effects were maintained at 7 days after initiating ANP infusion. Vasodilating, pulmonary vasorelaxant, and diuretic activities of ANP are maintained without tolerance, and thus long-term ANP infusion is clinically useful in patients with severe acute heart failure.

Role of platelet-activating factor on extravascular lung water after coronary reperfusion in dogs.

Platelet-activating factor (PAF), one of the harmful substances released after coronary reperfusion, has been reported to increase pulmonary vascular permeability and induce pulmonary edema. In this study, we sought to examine the possible role of PAF in the genesis of pulmonary edema after coronary reperfusion. Extravascular lung water (EVLW) was measured by the thermal-dye double indicator dilution method during coronary ligation and after reperfusion in situ in dogs. The proximal left anterior descending coronary artery was occluded for 15 min and reperfused in 5 dogs (group 1), while five other dogs (group 2) were treated with PAF-antagonist (TCV-309, 1 mg/kg) before coronary artery occlusion. EVLW and hemodynamic indices were measured at baseline, 15 min of coronary occlusion, and 15 and 30 min after coronary reperfusion. EVLW increased at 15 min of coronary occlusion in both groups, but there was no significant difference between the two groups (6.4 to 10.3 ml/kg and 5.4 to 7.1 ml/kg in groups 1 and 2, respectively). After coronary reperfusion, EVLW increased further in group 1 (6.4 to 16.5 ml/kg, p < 0.01), but no further increase was observed in group 2 at 30 min after coronary reperfusion. There were no significant differences in hemodynamic indices between the two groups throughout the test. Thus, PAF-antagonist attenuated the increase in EVLW after coronary reperfusion independent of hemodynamic indices, and hence, PAF may play an important role in the genesis of pulmonary edema caused by coronary reperfusion.

Clinical significance of the urinary oxygen tension in patients with ischemic heart disease.

The clinical significance of the urinary oxygen tension (PuO2) was evaluated in 60 patients with ischemic heart disease. The PuO2 had fair relations to cardiac index and serum creatinine level (r = 0.73 and r = 0.73, respectively). Although the PuO2 had a fair relation to serum creatinine in patients with a low cardiac index, there was no relation to the cardiac index. In patients with increases in PuO2 from day 1 to day 2, the cardiac index increased, and the serum creatinine level decreased on the 2nd day, whereas a sustained decrease in cardiac index and an increase in serum creatinine were observed in patients with a decrease in PuO2 from day 1 to day 2. Thus, PuO2 can be used as an indicator of the renal function in patients with ischemic heart disease.

Effects of platelet-activating factor on left ventricular performance in dogs.

To elucidate the mechanism by which platelet-activating factor (PAF) decreases cardiac output (CO), its effects on left ventricular (LV) performance were studied using a LV pressure-volume model in 9 anesthetized dogs. LV volume was measured with a conductance catheter and LV pressure with a manometer-tipped catheter. The slopes of the end-systolic pressure-volume (Ees), stroke work-end-diastolic volume (Mw), and arterial end-systolic pressure-stroke volume relations (Ea), and of end-diastolic pressure-volume relations (EDPVRs), were obtained to evaluate changes in LV performance. The time constant of isovolumetric relaxation (T) was computed by a logarithmic and a derivative method. After intravenous administration of PAF (1 microgram/kg), LV end-diastolic volume and pressure, end-systolic pressure, maximum dP/dt and CO decreased. Ees and Mw decreased significantly, minimum dP/dt decreased, and T increased. The arterial end-systolic pressure-stroke volume relation shifted leftward with an increase in the slope (Ea), whereas EDPVRs were shifted to the left and superimposed on their potential passive diastolic properties. These findings indicate the PAF decreases CO by reducing preload and contractility and by increasing arterial load. However, despite a prolongation of relaxation, PAF may not affect passive diastolic chamber stiffness.

The effects of infusion of trieicosapentaenoyl-glycerol emulsion on extravascular lung water during myocardial ischemia and reperfusion in dogs.

To test the effects of eicosapentaenoic acid (EPA) infusion on pulmonary edema induced by coronary ligation and reperfusion, extravascular lung water (EVLW) was measured in situ by the thermal-dye double indicator dilution method in dogs. In the control group of five dogs, 30 mL of a 10% soybean oil emulsion was infused through a leg vein. One hour after infusion, the left anterior descending coronary artery below the first diagonal branch was ligated for 15 min and then reperfused for 30 min. In the EPA group, six dogs were similarly treated with an emulsion of a 10% trieicosapentaenoyl-glycerol (90% pure). EVLW, pulmonary capillary wedge pressure, mean pulmonary artery pressure, mean blood pressure, and cardiac index were measured before and 15 min after coronary ligation, and 15 min and 30 min after coronary reperfusion. There were no significant differences in the hemodynamic indices between the two groups. EVLW significantly increased up to two times of baseline during coronary ligation in the control group (P < 0.05) and more during reperfusion (P < 0.01), whereas EVLW did not increase in the EPA group. In conclusion, EPA inhibited EVLW accumulation and may be useful for ameliorating one of the ischemia-reperfusion-induced complications, pulmonary edema.

Monitoring urine oxygen tension during acute change in cardiac output in dogs.

To evaluate whether renal blood flow (RBF) can be monitored during acute change in cardiac index, ureter urine oxygen tension (PuO2) and bladder urine oxygen tension (PbO2) were measured in six mongrel dogs. PuO2, cardiac index, and RBF increased after dobutamine infusion and decreased after propranolol infusion. PuO2 had an excellent correlation with RBF (r = 0.94) and a fair correlation with cardiac index (r = 0.50) and mean blood pressure (r = 0.56); RBF had a fair correlation with mean blood pressure (r = 0.52, P < 0.05) but was not related to cardiac index. With multiple-regression analysis, PuO2 was found to be the significant factor related to RBF. PbO2 had a good correlation with PuO2 (r = 0.94) at control levels. Furthermore, when two dogs were added to evaluate relationships among PbO2, PuO2, and RBF, PbO2 had an excellent correlation with PuO2 (r = 0.92) and RBF (r = 0.91). These data indicate that PuO2 is a more sensitive predictor of RBF than cardiac index and mean blood pressure and that PbO2 can be a noninvasive indicator reflecting RBF during acute circulatory change in dogs.

Effect of atrial and ventricular activation interval on hemodynamics during atrioventricular and ventriculoatrial pacing: determination from pressure-volume loops in dogs.

To determine the effect of relative timing of atrial and ventricular activation on hemodynamic indices, we evaluated pressure-volume loops during pacing at 160 beats/min with various atrioventricular intervals in dogs. End-systolic pressure, end-diastolic volume, and stroke volume were reduced during pacing at atrioventricular intervals of 0 ms, compared with 80 ms. These changes were more significant during pacing at atrioventricular intervals of -50 and -100 ms than at 0 ms. During tachycardia, the abnormal timing of atrial contraction leads to unfavorable hemodynamic change and the degree of the changes are determined by the ventriculoatrial activation interval.

The effect of platelet-activating-factor antagonist TCV-309 on arrhythmias and functional recovery during myocardial reperfusion.

BACKGROUND: We investigated the effects of a platelet-activating-factor antagonist TCV-309, an antagonist of metabolites of ischemia, on arrhythmias and functional recovery during in-situ reperfusion in dogs. METHODS: Open-chest anesthetized dogs were subjected to ligation of the left anterior coronary artery. Ischemia was maintained for 20 min after which reperfusion was allowed. A cardiac surface ECG was recorded continuously with the II limb lead. Monophasic action potential, left ventricular segment shortening measured by sonomicrometer, and left ventricular pressure were recorded simultaneously under atrial pacing (group A, n = 14). In a second group of dogs, TCV-309 (1 mg/kg) was administered before coronary artery occlusion (group B, n = 12). The hearts were constantly paced through the right atrium at 120 beats/min throughout all experiments. Measurements were continuously obtained from before drug administration to 30 min after reperfusion. RESULTS: The 90% repolarization time of monophasic action potentials in group B revealed significant recovery compared with group A until the fifth minute after reperfusion (P < 0.02). Reduction of severe ventricular arrhythmias was observed during reperfusion in group B (P < 0.05). The percentage segment shortening and left ventricular pressure did not differ significantly between the groups. CONCLUSION: The platelet-activating-factor antagonist had beneficial effects on arrhythmias but not on functional recovery during reperfusion after brief coronary artery occlusion in situ in dogs.

Effect of the leukotriene receptor antagonist ONO-1078 on extravascular lung water after coronary ligation in dogs.

To determine whether or not leukotrienes are associated with pulmonary edema after coronary ligation in dogs, we studied the effects of a specific leukotriene C4/D4 antagonist, ONO-1078, on extravascular lung water, as measured by the thermal-dye double indicator dilution method (Extravascular thermal volume, ETV). Six dogs served as a sham control (group 1). The proximal left anterior descending coronary artery was ligated for 45 min in 6 dogs (group 2), and in 6 others the coronary artery was ligated after pretreatment with ONO-1078 (1 mu/kg/min) (group 3). ETV and pulmonary arterial pressure were measured at control and 45 min after coronary ligation. In group 1, no significant change was found in ETV. Although there was no significant increase in pulmonary arterial pressure after coronary ligation, ETV significantly increased in groups 2 and 3. ETV increased more in groups 2 and 3 than in group 1, but there was no significant difference between groups 2 and 3. Thus, ONO-1078 did not effectively prevent the accumulation of extravascular lung water after coronary ligation, indicating that leukotrienes are not important mediators of pulmonary edema after myocardial ischemia.

Clinical significance of serum colloid osmotic pressure in relation to pulmonary edema and coronary instability in patients with unstable angina.

Several investigators demonstrated that severe reduction of colloid osmotic pressure (COP) predicts a fatal outcome in patients with cardiopulmonary failure. To evaluate the clinical significance of COP in relation to pulmonary edema, we studied 117 patients with unstable angina admitted in the hospital within 24 h after the chest pain. The mean COP of all 117 patients was 24.8 +/- 3.7 mmHg. COP was significantly lower in patients with pulmonary edema, according to the chest x-ray findings, compared with the patients without it. Among 26 patients with emergency coronary arteriography, a fairly good correlation was observed between coronary jeopardy score and COP (r = -0.57, p less than 0.005). Furthermore, COP in patients who survived 26 months after the hospital discharge was significantly higher than that of the nonsurvivors. Thus, measurement of COP is advised for monitoring patients with unstable angina.

[Clinical characteristics of pulmonary edema in patients with unstable angina].

To elucidate the clinical characteristics of pulmonary edema in unstable angina, 120 patients with unstable angina who admitted to the hospital within 6 hours after the onset of chest pain were studied. The criteria for the diagnosis of pulmonary edema included interstitial pulmonary edema and diffuse alveolar edema. Pulmonary edema was present in 24 patients. In these patients, the duration of chest pain was relatively longer, and the incidences of diabetes mellitus, emergency coronary revascularization and multiple-vessel coronary artery disease were higher than in those without pulmonary edema. In addition, in-hospital mortality rate in patients with pulmonary edema was higher than in those without it (21 vs 1%, p < 0.001), which is probably due to a large area of myocardial ischemia. For these patients, therefore, early diagnosis and appropriate therapy to save viable segments of the myocardium are mandatory.